The purpose of this study is to evaluate the variations in exhaled CO and saliva cotinine in natural environment waterpipe smokers and compare them with cigarette smokers and absolute nonsmokers. Three groups were included in the study: nonsmokers (n = 20), waterpipe smokers (n = 15), and cigarette smokers (n = 20). A questionnaire was completed for each participant, exhaled CO was measured before and after waterpipe or cigarette smoking, and saliva cotinine was measured immediately after. We excluded from our study mixed smokers of both waterpipe and cigarettes. Mean values of saliva cotinine in waterpipe and cigarette smokers were very close: 77.8 ng/ml (SD = 110.4) and 87.1 (SD = 82.7) respectively. The weight and height of the persons as well as the size of the waterpipe bottle affected saliva cotinine. However, in waterpipe smokers, CO increased by 300% after 1 h of smoking, while in cigarette smokers, it only increased by 60%. In nonsmokers, exhaled CO was similar to environmental CO (10.2 ppm). The results of our study confirm that waterpipe device water does not filter nicotine and that the smoker him- or herself, by the frequency and the depth of inhalation, controls smoke inhalation. Like cigarette smokers, waterpipe smokers are exposed to harmful substances, such as CO, which was found to be quite high. The levels of expired CO and salivary cotinine could be good tools to detect exposure to waterpipe smoking.